A new animal model of systemic sclerosis

2013 Fiscal Year Final Research Report

• Project/Area Number: 24659522
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Dermatology
• Research Institution: The University of Tokyo
• Principal Investigator: SATO Shinichi 東京大学, 医学部附属病院, 教授 (20215792)
• Co-Investigator(Kenkyū-buntansha): ASANO Yoshihide 東京大学, 医学部附属病院, 講師 (60313029)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Keywords: 全身性強皮症 / トポイソメラーゼI / 完全フロイドアジュバンド / IL-6 / 皮膚硬化 / 肺線維化 / 自己免疫

Research Abstract

To assess the contribution of anti-DNA topoisomerase I(anti-topo I)antibody, tissue fibrosis and cytokine production were examined in mice treated with topo I and either Freund's complete adjuvant (CFA) or Freund's incomplete adjuvant(IFA).
Treatment with topo I and CFA,in contrast to treatment with topo I and IFA,induced skin and lung fibrosis with increased interleukin (IL)-6 and IL-17 production. Anti-topo I antibody levels were greater in mice treated with topo I and CFA than with topo I and IFA.Furthermore,treatment with topo I and CFA increased Th2 and Th17 cell frequencies in bronchoalveolar lavage fluid,whereas treatment with topo I and IFA increased Th1 and Treg cell frequencies.Moreover,loss of IL-6 expression ameliorated skin and lung fibrosis and decreased Th2 and Th17 cell frequencies. This study shows that treatment with topo I and CFA induces SSc-like tissue fibrosis and autoimmunity.

Research Products

• [Journal Article] Serum apelin levels : clinical association with vascular involvements in patients with systemic sclerosis (2013)
  • Author(s): Aozasa N, Asano Y, Akamata K, Noda S, Masui Y, Yamada D, Tamaki Z, Tada Y, Sugaya M, Kadono T, Sato S.
  • Journal Title: J Eur Acad Dermatol Venereol Volume: 27(1) Pages: 37-42
• [Journal Article] Serum levels of ADAM12-S : possible association with the initiation and progression of dermal fibrosis and interstitial lung disease in patients with systemic sclerosis (2013)
  • Author(s): Taniguchi T, Asano Y, Akamata K, Aozasa N, Noda S, Takahashi T, Ichimura Y, Toyama T, Sumida H, Kuwano Y, Yanaba K, Tada Y, Sugaya M, Kadono T, Sato S.
  • Journal Title: J Eur Acad Dermatol Venereol Volume: 27(6) Pages: 747-753
• [Journal Article] The dynamics of serum angiopoietin-2 levels correlates with the efficacy of intravenous cyclophosphamide pulse for interstitial lung disease associated with systemic sclerosis (2013)
  • Author(s): Takahashi T, Asano Y, Akamata K, Aozasa N, Taniguchi T, Noda S, Masui Y, Ichimura Y, Toyama T, Tamaki Z, Tada Y, Sugaya M, Kadono T, Sato S.
  • Journal Title: Mod Rheumatol Volume: 23(5) Pages: 884-890
• [Journal Article] Clinical significance of serum retinol binding protain-4 levels in patients with systemic sclerosis (2013)
  • Author(s): Toyama T, Asano Y, Takahashi T, Aozasa N, Akamata K, Noda S, Taniguchi T, Ichimura Y, Sumida H, Tamaki Z, Masui Y, Tada Y, Sugaya M, Sato S, Kadono T.
  • Journal Title: J Eur Acad Dermatol Venereol Volume: 27(3) Pages: 337-344
• [Journal Article] A randomized, double-blind, placebo-controlled trial : intravenous immunoglobulin treatment in patients with diffuse cutaneous systemic sclerosis (2013)
  • Author(s): Takehara K, Ihn H, Sato S.
  • Journal Title: Clin Exp Rheumatol Volume: 31(2 Suppl 76) Pages: 151-156
• [Journal Article] A possible contribution of decreased cathepsin V expression caused by Fli deficiency to the development of dermal fibrosis and proliferative vasculopathy in systemic sclerosis (2013)
  • Author(s): Noda S, Asano Y, Takahashi T, Akamata K, Aozasa N, Taniguchi T, Ichimura Y, Toyama T, Sumida H, Kuwano Y, Yanaba K, Tada Y, Sugaya M, Kadono T, Sato S.
  • Journal Title: Rheumatology Volume: 52(5) Pages: 790-799
• [Journal Article] Serum chemokine levels as prognostic markers in patients with early systemic sclerosis : a multicenter,prospective,observational study (2013)
  • Author(s): Hasegawa M, Asano Y, Endo H, Fujimoto M, Goto D, Ihn H, Inoue K, Ishikawa O, Kawaguchi Y, Kuwana M, Ogawa F, Takahashi H, Tanaka S, Sato S, Takehara K.
  • Journal Title: Mod Rheum Volume: 23(6) Pages: 1076-1084
• [Journal Article] Serum angiopoietin-like protein 3 levels : a possible correlation with progressive skin sclerosis, digital ulcers, and pulmonary vascular involvement in patients with systemic sclerosis (2013)
  • Author(s): Ichimura Y, Asano Y, Akamata K, Aozasa N, Noda S, Taniguchi T, Takahashi T, Toyama T, Sumida H, Kuwano Y, Yanaba K, Tada Y, Sugaya M, Sato S, Kadono T.
  • Journal Title: Acta Derm-Venereol Volume: (Epub ahead of point)
• [Journal Article] Fli1 deficiency contributes to the suppression of endothelial CXCL5 expression in systemic sclerosis (2013)
  • Author(s): Ichimura Y, Asano Y, Akamata K, Takahashi T, Noda S, Taniguchi T, Toyama T, Aozasa N, Sumida H, Kuwano Y, Yanaba K, Tada Y, Sugaya M, Sato S, Kadono T.
  • Journal Title: Arch Dermatol Res Volume: (Epub ahead of point)
• [Journal Article] A possible contribution of visfatin to the resolution of skin sclerosis in patients with diffuse cutaneous systemic sclerosis via a direct anti-fibrotic effect on dermal fibroblasts and Th1 polarization of the immune response (2013)
  • Author(s): Masui Y, Asano Y, Shibata S, Noda S, Akamata K, Aozasa N, Taniguchi T, Takahashi T, Ichimura Y, Toyama T, Sumida H, Yanaba K, Tada Y, Sugaya M, Sato S, Kadono T.
  • Journal Title: Rheumatology (Oxford) Volume: 52 Pages: 1239-1244
• [Journal Article] Serum resistin levels : a possible correlation with pulmonary vascular involvement in patients with systemic sclerosis (2013)
  • Author(s): Masui Y, Asano Y, Akamata K, Aozasa N, Noda S, Taniguchi T, Takahashi T, Ichimura Y, Toyama T, Sumida H, Kuwano Y, Yanaba K, Tada Y, Sugaya M, Sato S, Kadono T.
  • Journal Title: Rheumatol Int Volume: (Epub ahead of point)
• [Journal Article] Presence of desaturated hemoglobin enhances the contribution of blood cells to flow-mediated dilation in subjects with systemic sclerosis (2013)
  • Author(s): Amiya E, Takata M, Watanabe M, Takahashi T, Asano Y, Hatano M, Ozeki A, Watanabe A, Kawarasaki S, Tamaki Z, Taniguchi T, Ichimura Y, Toyama T, Nagai R, Sato S, Komuro I.
  • Journal Title: Int J Cardiol Volume: 168(3) Pages: 3125-3127
• [Journal Article] Serum levels of galectin-3 : possible association with fibrosis, aberrant angiogenesis, and immune activation in patients with systemic sclerosis (2012)
  • Author(s): Taniguchi T, Asano Y, Akamata K, Noda S, Masui Y, Yamada D, Takahashi T, Ichimura Y, Toyama T, Tamaki Z, Tada Y, Sugaya M, Kadono T, Sato S.
  • Journal Title: J Rheumato Volume: l39(3) Pages: 539-544
• [Journal Article] Effects of bosentan on non-digital ulcers in patients with systemic sclerosis (2012)
  • Author(s): Taniguchi T, Asano Y, Hatano M, Tamaki Z, Tomita M, Kawashima T, Miyazaki M, Sumida H, Akamata K, Takahashi T, Ichimura Y, Toyama T, Sugita M, Noda S, Yao A, Kinugawa K, Sato S.
  • Journal Title: Br J Dermatol Volume: 166(2) Pages: 417-421
• [Journal Article] Serum levels of soluble CD21 in patients with systemic sclerosis (2012)
  • Author(s): Tomita M, Kaodono T, Yazawa N, Kawashima T, Tamaki Z, Ashida R, Ohmatsu H, Asano Y, Sugaya M, Kubo M, Ihn H, Tamaki K, Sato S.
  • Journal Title: Rheumatol Int Volume: 32(2) Pages: 317-321
• [Journal Article] Serum adiponectin levels inversely correlate with the activity of progressive skin sclerosis in patients with diffuse cutaneous systemic sclerosis (2012)
  • Author(s): Masui Y, Asano Y, Shibata S, Noda S, Aozasa N, Akamata K, Yamada D, Tamaki Z, Tada Y, Sugaya M, Sato S, Kadono T.
  • Journal Title: J Eur Acad Dermatol Venereol Volume: 26(3) Pages: 354-360
• [Journal Article] Clinical significance of serum growth differentiation factor-15 levels in systemic sclerosis : association with disease severity (2012)
  • Author(s): Yanaba K, Asano Y, Tada Y, Sugaya M, Kadono T, Sato S.
  • Journal Title: Mod Rheumatol Volume: 22(5) Pages: 668-675
• [Journal Article] Clinical significance of circulating platelet-activating factor acetylhydrolase levels in systemic sclerosis (2012)
  • Author(s): Yanaba K, Asano Y, Tada Y, Sugaya M, Kadono T, Sato S.
  • Journal Title: Arch Dermatol Res Volume: 304(3) Pages: 203-208
• [Journal Article] Investigation of prognostic factors for skin sclerosis and lungfunction in Japanese patients with early systemic prospect observational study.sclerosis : a multicentre (2012)
  • Author(s): Hasegawa M, Asano Y, Endo H, Fujimoto M, Goto D, Ihn H, Inoue K, Ishikawa O, Kawaguchi Y, Kuwana M, Muro Y, Ogawa F, Sasaki T, Takahashi H, Tanaka S, Takehara K, Sato S.
  • Journal Title: Rheumatology (Oxford) Volume: 51(1)
• [Journal Article] Association of UBE2L3 polymorphisms with diffuse cutaneous systemic sclerosis in a Japanese population (2012)
  • Author(s): Hasebe N, Kawasaki A, Ito I, Kawamoto M, Hasegawa M, Fujimoto M, Furukawa H, Tohma S, Sumida T, Takehara K, Sato S, Kawaguchi Y, Tsuchiya N.
  • Journal Title: Ann Rheum Dis Volume: 71(7) Pages: 1259-1260
• [Journal Article] A possible contribution of altered cathepsin B expression to the development of skin sclerosis and vasculopathy in systemic sclerosis (2012)
  • Author(s): Noda S, Asano Y, Akamata K, Aozasa N, Taniguchi T, Takahashi T, Ichimura Y, Toyama T, Sumida H, Yanaba K, Tada Y, Sugaya M, Kadono T, Sato S.
  • Journal Title: PLos One Volume: 7(2) Pages: e32272
• [Journal Article] Clinical significance of serum levels of secretory leukocyte protease inhibitor in patients with systemic sclerosis (2012)
  • Author(s): Aozasa N, Asano Y, Akamata K, Noda S, Masui Y, Tamaki Z, Tada Y, Sugaya M, Kadono T, Sato S.
  • Journal Title: Mod Rheumatol Volume: 22(4) Pages: 576-583
• [Journal Article] Increased serum soluble CD147 levels in patients with systemic sclerosis : association with scleroderma renal crisis (2012)
  • Author(s): Yanaba K, Asano Y, Tada Y, Sugaya M, Kadono T, Hamaguchi Y, Sato S.
  • Journal Title: Clin Rheumatol Volume: 31(5) Pages: 835-839
• [Journal Article] A possible contribution of elevated serum clusterin levels to the development of digital ulcers and pulmonary arterial hypertension in systemic sclerosis (2012)
  • Author(s): Yanaba K, Asano Y, Tada Y, Sugaya M, Kadono T, Sato S.
  • Journal Title: Arch Dermatol Res Volume: 304(6) Pages: 459-463
• [Journal Article] Clinical significance of serum decoy receptor 3 levels in patints with systemic sclerosis (2012)
  • Author(s): Yamada D, Asano Y, Takahashi T, Masui Y, Aozasa N, Akamata K, Noda S, Tamaki Z, Tada Y, Sugaya M, Sato S, Kadono T.
  • Journal Title: Eur J Dermatol Volume: 22(3) Pages: 351-357
• [Journal Article] Augmented production of soluble CD93 in patients with systemic sclerosis and clinical association with severity of skin sclerosis (2012)
  • Author(s): Yanaba K, Asano Y, Noda S, Akamata K, Aozasa N, Taniguchi T, Takahashi T, Ichimura Y, Toyama T, Sumida H, Kuwano Y, Tada Y, Sugaya M, Kadono T, Sato S.
  • Journal Title: Br J Dermatol Volume: 167(3) Pages: 542-547
• [Journal Article] Constitutive activation of c-Abl/protein kinase C-δ/Fli pathway in dermal fibroblasts derived from patients with localized scleroderma (2012)
  • Author(s): Noda S, Asano Y, Akamata K, Aozasa N, Taniguchi T, Takahashi T, Ichimura Y, Toyama T, Sumida H, Yanaba Y, Tada Y, Sugaya M, Kadono T, Sato S.
  • Journal Title: Br J Dermatol Volume: 167(5) Pages: 1098-1105
• [Journal Article] Clinical significance of monitoring serum adiponectin levels during intravenous pulse cyclophosphamide therapy in interstitial lung disease associated with systemic sclerosis (2012)
  • Author(s): Masui Y, Asano Y, Takahashi T, Shibata S, Akamata K, Aozasa N, Noda S, Taniguchi T, Ichimura Y, Toyama T, Tamaki Z, Sumida H, Yanaba K, Tada Y, Sugaya M, Sato S, Kadono T.
  • Journal Title: 2012 Mod Rheumatol Volume: 23(2) Pages: 323-329